A novel mitochondrial tRNAGlu (MTTE) gene mutation causing chronic progressive external ophthalmoplegia at low levels of heteroplasmy in muscle

Alston, Charlotte L.; Lowe, James; Turnbull, Doug M.; Maddison, Paul; Taylor, Robert W.

doi:10.1016/j.jns.2010.08.014

Cited by 11 publications

(7 citation statements)

References 23 publications

(26 reference statements)

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“…So far, disease causing D-stem variants are reported for 16 of the 22 mt-tRNA genes, and are associated with a wide range of clinical presentations (Supplementary Table 1). Some of these mt-tRNA D -stem cases have a relatively low (18-38%) muscle mutation load and clearly show phenotypical overlap with our patient, displaying relatively mild symptoms (mainly CPEO, ptosis, myopathy) with an age of onset at 26-66 years [13][14][15][16][17] . As compared to other pathogenic variants in the tRNA Met gene (summarized in [18] ) our patient has a much lower muscle heteroplasmy level, probably responsible for the milder phenotype and later onset of disease than the other reported MT-TM patients.…”

Section: Discussionsupporting

confidence: 53%

A novel mitochondrial m.4414T>C MT-TM gene variant causing progressive external ophthalmoplegia and myopathy

Hellebrekers

Blakely

Hendrickx

et al. 2019

Neuromuscular Disorders

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We report a novel mitochondrial m.4414T > C variant in the mt-tRNA Met (MT-TM) gene in an adult patient with chronic progressive external ophthalmoplegia and myopathy whose muscle biopsy revealed focal cytochrome c oxidase (COX)-deficient and ragged red fibres. The m.4414T > C variant occurs at a strongly evolutionary conserved sequence position, disturbing a canonical base pair and disrupting the secondary and tertiary structure of the mt-tRNA Met. Definitive evidence of pathogenicity is provided by clear segregation of m.4414T > C mutant levels with COX deficiency in single muscle fibres. Interestingly, the variant is present in skeletal muscle at relatively low levels (30%) and undetectable in accessible, non-muscle tissues from the patient and her asymptomatic brother, emphasizing the continuing requirement for a diagnostic muscle biopsy as the preferred tissue for mtDNA genetic investigations of mt-tRNA variants leading to mitochondrial myopathy.

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Section: Discussionsupporting

confidence: 53%

A novel mitochondrial m.4414T>C MT-TM gene variant causing progressive external ophthalmoplegia and myopathy

Hellebrekers

Blakely

Hendrickx

et al. 2019

Neuromuscular Disorders

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“… 17 These assays have been established in the Newcastle laboratory for a variety of pathogenic mutations and have been shown to be sensitive in their detection of 1% mutation load. 18 , 19 , 20 , 21 Mutation screening for large-scale single mtDNA deletions is performed using a combined methodology involving quantitative fluorescent real-time PCR (QPCR) and long-range PCR. 22 The QPCR assay compares the copy number of the commonly deleted MTND4 gene against the copy number of the MTND1 gene, which is seldom deleted in patients with large-scale mtDNA rearrangements.…”

Section: Methodsmentioning

confidence: 99%

A national perspective on prenatal testing for mitochondrial disease

Nesbitt

Alston²,

Blakely³

et al. 2014

Eur J Hum Genet

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Mitochondrial diseases affect >1 in 7500 live births and may be due to mutations in either mitochondrial DNA (mtDNA) or nuclear DNA (nDNA). Genetic counselling for families with mitochondrial diseases, especially those due to mtDNA mutations, provides unique and difficult challenges particularly in relation to disease transmission and prevention. We have experienced an increasing demand for prenatal diagnostic testing from families affected by mitochondrial disease since we first offered this service in 2007. We review the diagnostic records of the 62 prenatal samples (17 mtDNA and 45 nDNA) analysed since 2007, the reasons for testing, mutation investigated and the clinical outcome. Our findings indicate that prenatal testing for mitochondrial disease is reliable and informative for the nuclear and selected mtDNA mutations we have tested. Where available, the results of mtDNA heteroplasmy analyses from other family members are helpful in interpreting the prenatal mtDNA test result. This is particularly important when the mutation is rare or the mtDNA heteroplasmy is observed at intermediate levels. At least 11 cases of mitochondrial disease were prevented following prenatal testing, 3 of which were mtDNA disease. On the basis of our results, we believe that prenatal testing for mitochondrial disease is an important option for couples where appropriate genetic analyses and pre/post-test counselling can be provided.

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“…The quantitation of mutated mitochondrial DNA heteroplasmy levels for point mutations including m.3243A>G, m.8344A>G and m.13094T>C was performed using PyroMark™ Q24 platform (Qiagen) as previously described (Alston et al ., 2010; Lax et al ., 2012 a ). …”

Section: Methodsmentioning

confidence: 99%

Microangiopathy in the cerebellum of patients with mitochondrial DNA disease

Lax

Pienaar

Reeve

et al. 2012

Brain

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Neuropathological findings in mitochondrial DNA disease vary and are often dependent on the type of mitochondrial DNA defect. Many reports document neuronal cell loss, demyelination, gliosis and necrotic lesions in post-mortem material. However, previous studies highlight vascular abnormalities in patients harbouring mitochondrial DNA defects, particularly in those with the m.3243A>G mutation in whom stroke-like events are part of the mitochondrial encephalopathy lactic acidosis and stroke-like episodes syndrome. We investigated microangiopathic changes in the cerebellum of 16 genetically and clinically well-defined patients. Respiratory chain deficiency, high levels of mutated mitochondrial DNA and increased mitochondrial mass were present within the smooth muscle cells and endothelial cells comprising the vessel wall in patients. These changes were not limited to those harbouring the m.3243A>G mutation frequently associated with mitochondrial encephalopathy, lactic acidosis and stroke-like episodes, but were documented in patients harbouring m.8344A>G and autosomal recessive polymerase (DNA directed), gamma (POLG) mutations. In 8 of the 16 patients, multiple ischaemic-like lesions occurred in the cerebellar cortex suggestive of vascular smooth muscle cell dysfunction. Indeed, changes in vascular smooth muscle and endothelium distribution and cell size are indicative of vascular cell loss. We found evidence of blood–brain barrier breakdown characterized by plasma protein extravasation following fibrinogen and IgG immunohistochemistry. Reduced immunofluorescence was also observed using markers for endothelial tight junctions providing further evidence in support of blood–brain barrier breakdown. Understanding the structural and functional changes occurring in central nervous system microvessels in patients harbouring mitochondrial DNA defects will provide an important insight into mechanisms of neurodegeneration in mitochondrial DNA disease. Since therapeutic strategies targeting the central nervous system are limited, modulating vascular function presents an exciting opportunity to lessen the burden of disease in these patients.

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A novel mitochondrial tRNAGlu (MTTE) gene mutation causing chronic progressive external ophthalmoplegia at low levels of heteroplasmy in muscle

Cited by 11 publications

References 23 publications

A novel mitochondrial m.4414T>C MT-TM gene variant causing progressive external ophthalmoplegia and myopathy

A novel mitochondrial m.4414T>C MT-TM gene variant causing progressive external ophthalmoplegia and myopathy

A national perspective on prenatal testing for mitochondrial disease

Microangiopathy in the cerebellum of patients with mitochondrial DNA disease

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